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Abstract Details
Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study
Robin Kate Kelley1, Bruno Sangro2, William Harris3, Masafumi Ikeda4, Takuji Okusaka5, Yoon-Koo Kang6, Shukui Qin7, David W-M Tai8, Ho Yeong Lim9, Thomas Yau10, Wei-Peng Yong11, Ann-Lii Cheng12, Antonio Gasbarrini13, Silvia Damian14, Jordi Bruix15, Mitesh Borad16, Johanna Bendell17, Tae-You Kim18, Nathan Standifer19, Philip He20, Mallory Makowsky20, Alejandra Negro20, Masatoshi Kudo21, Ghassan K Abou-Alfa2223
Author information
1University of California, San Francisco, CA.
2Liver Unit, Clínica Universidad de Navarra, IdiSNA and CIBEREHD, Pamplona, Spain.
3University of Washington, Seattle, WA.
4National Cancer Center Hospital East, Kashiwa, Japan.
5National Cancer Center Hospital, Tokyo, Japan.
6Department of Oncology, Asan Medical Center (AMC), University of Ulsan, Seoul, South Korea.
7Cancer Center of Nanjing, Jinling Hospital, Nanjing, China.
8National Cancer Centre Singapore, Singapore.
9Samsung Medical Center (SMC), Sungkyunkwan University, Seoul, South Korea.
10Queen Mary Hospital, Pok Fu Lam, Hong Kong.
11National University Cancer Institute Singapore (NCIS), Singapore.
12National Taiwan University (NTU), Taipei, Taiwan.
13Catholic University of the Sacred Heart, Milan, Italy.
14Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
15Barcelona Clinic Liver Cancer (BCLC), Hospital Clinic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
16Mayo Clinic Cancer Center, Phoenix, AZ.
17Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN.
18Seoul National University Hospital, Seoul, South Korea.
19AstraZeneca, South San Francisco, CA.
20AstraZeneca, Gaithersburg, MD.
21Faculty of Medicine, Kindai University, Osaka, Japan.
22Memorial Sloan Kettering Cancer Center, New York, NY.
23Weill Cornell Medicine, Cornell University, New York, NY.
Abstract
Purpose: This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348).
Patients and methods: Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles.
Results: A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively.
Conclusion: All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.